Future perspectiveA comprehensive understanding of the overall impact of viral and host factors that modulate HIV persistence is critical in developing curative strategies for HIV infection. Gal-9 is one of the endogenous host immune-modulatory factors that has been recently associated with opposing effects on HIV infection. Several studies have highlighted the potential beneficial effects of Gal-9 during HIV infection. First, Gal-9 renders CD4+ T cells less susceptible to HIV infection via induction of the host restriction factor cyclin-dependent kinase inhibitor 1 (p21) 8). Second, recombinant Gal-9 induces HIV transcription and reverses HIV latency in vitro and ex vivo. This ability of Gal-9 to induce latent HIV transcription suggested that it could be considered within the “shock and kill” HIV eradication framework 1,2). However, on the other hand, several other studies have highlighted the detrimental effects of Gal-9 during HIV infection. First, endogenous Gal-9 is rapidly increased after HIV infection 4). These elevated levels of Gal-9 do not return to normal after suppressive ART 4) and are associated with higher HIV transcription in vivo in plasma of HIV-infected, ART-suppressed individuals 1). Second, Gal-9 can increase HIV entry by inducing the CD4+ T cell-surface concentration of protein disulfide isomerase (PDI) 9). Finally, Gal-9 modulates HIV transcription by activating the TCR-downstream signaling pathways 3), and several recent studies linked Gal-9 may contribute to the state of chronic immune activation and inflammation during HIV infection 5-7). In this study, we sought to evaluate whether the overall impact of Gal-9 on HIV persistence is beneficial or detrimental in vivo. Using a physiological-relevant animal model of HIV infection, the BLT humanized mice; we found that Gal-9 can directly expand HIV reservoirs and exhibits overall adverse effects on HIV persistence and that these effects would limit the potential use of Gal-9 as a shock and kill agent. Our data also show that the Gal-9-mediated expansion of HIV reservoirs is not linked to T cell activation or systemic inflammation. However, Gal-9 can induce T cell proliferation 1), which might be linked to its modulation of HIV persistence. Furthermore, Gal-9 can impact many aspects of immune responses relevant to persistence. For example, Gal-9 exhibits several immunosuppressive activities, including the ability to increase the function of regulatory T cells (T-regs) and to impair Natural Killer cells (NK) cytotoxicity. The potential link between Gal-9-mediated impact on T cell proliferation or immune functions and its ability to expand HIV reservoirs warrants a broader investigation. Gal-9 is highly abundant in vivo, especially during HIV infection 4), and its levels have been associated, during ART-suppressed HIV infection, with the state of chronic inflammation and immune activation that is central to the development of several HIV-associated co-morbidities. Therefore, clarifying the mechanistic underpinnings of the overall adverse effects of Gal-9 during ART-suppressed HIV infection may lead to the development of interventions to target Gal-9 (such as anti-Gal-9 antibodies and small molecule inhibitors targeting Gal-9 10)) to improve immune functionality, reduce inflammation-associated co-morbidities, and reduce levels of HIV persistence, in the setting of viral suppression by ART. 1) Abdel-Mohsen M, Chavez L, Tandon R, Chew GM, Deng X, Danesh A, et al. Human Galectin-9 Is a Potent Mediator of HIV Transcription and 2) Sanz M, Madrid-Elena N, Serrano-Villar S, Vallejo A, Gutierrez C, Moreno S. Effect of the use of Galectin-9 and blockade of TIM-3 receptor in the latent 3) Colomb F, Giron LB, Premeaux TA, Mitchell BI, Niki T, Papasavvas E, et al. Galectin-9 Mediates HIV Transcription by Inducing TCR-Dependent ERK 4) Tandon R, Chew GM, Byron MM, Borrow P, Niki T, Hirashima M, et al. Galectin-9 is rapidly released during acute HIV-1 infection and remains 5) Dunsmore G, Rosero EP, Shahbaz S, Santer DM, Jovel J, Lacy P, et al. Neutrophils promote T-cell activation through the regulated release of CD44- 6) Premeaux TA, D'Antoni ML, Abdel-Mohsen M, Pillai SK, Kallianpur KJ, Nakamoto BK, et al. Elevated cerebrospinal fluid Galectin-9 is associated with 7) Premeaux TA, Moser CB, McKhann A, Hoenigl M, Laws EI, Aquino DL, et al. Plasma galectin-9 as a predictor of adverse non-AIDS events in persons 8) Elahi S, Niki T, Hirashima M, Horton H. Galectin-9 binding to Tim-3 renders activated human CD4+ T cells less susceptible to HIV-1 infection. Blood 9) Schaefer K, Webb NE, Pang M, Hernandez-Davies JE, Lee KP, Gonzalez P, et al. Galectin-9 binds to O-glycans on protein disulfide isomerase. Reactivation. PLoS Pathog 2016; 12(6):e1005677.cellular reservoir of HIV-1. J Virol 2020.Signaling. Front Immunol 2019; 10:267.sustained at high levels despite viral suppression even in elite controllers. AIDS Res Hum Retroviruses 2014; 30(7):654-664.bound Galectin-9 from the cell surface during HIV infection. PLoS Biol 2021; 19(8):e3001387.central nervous system immune activation and poor cognitive performance in older HIV-infected individuals. J Neurovirol 2019; 25(2):150-161.with chronic HIV during suppressive antiretroviral therapy. AIDS 2021; 35(15):2489-2495.2012; 119(18):4192-4204.Glycobiology 2017; 27(9):878-887.10) Yang R, Sun L, Li CF, Wang YH, Xia W, Liu B, et al. Development and characterization of anti-galectin-9 antibodies that protect T cells from galectin-9-induced cell death. J Biol Chem 2022; 298(4):101821.T cell activation or systemic inflammation.References101
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